Among the viruses responsible for the many and diverse viral diseases, a type of viruses known as opportunistic viruses can be distinguished, that are characterized because, although they may affect the general population, the occurrence of their infections is particularly high in individuals with impaired immune system, for example, in patients infected with the human immunodeficiency virus (HIV) or in transplanted patients, in which their pathological effects are manifested in a particularly virulent way.
Among the viruses usually included within the group of opportunistic viruses are mainly herpesvirus and human papillomavirus, as well as Molluscum contagiosum virus, hepatitis B virus, hepatitis C virus, JC virus, and BK virus, as described, for example, in the publications Salavert et al. Role of viral infections in immunosuppressed patients, Med. Intensiva, 2011, 35 (2), pp 117-125; and U. Banarjee, Progress in diagnosis of opportunistic infections in HIV/AIDS, Indian J. Med. Res., 2005, 121, pp 395-406.
Herpesviruses belong to the Herpesviridae family, and are DNA viruses. They are composed of a DNA strand surrounded by an icosahedral capsid; it, in turn, is surrounded by a tegument and a membrane arranged as an envelope.
Eight different species have been identified among the herpesviruses: herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (HCMV) and herpesvirus type 6 (HHV-6), 7 (HHV-7) and 8 or Kaposi's Sarcoma herpesvirus (HHV-8, KSHV).
All of them share the common feature that, after infection, they may remain in a latent state, alternating latent periods with reactivation periods throughout the whole life of the infected individual. The latency period is characterized by a minimal expression of the viral gene and the absence of synthesis of new viruses.
Usually a distinction can be drawn between primary infection, referred to the first infection of the subject by the virus, which usually occurs in childhood or adolescence and which is often asymptomatic, and the subsequent reactivations which lead to recurrent injuries.
Diseases caused by herpesvirus infection are diverse due to the variety of the viruses and also because most of them can interact with the infected patient in more than one way and cause more than one pathology.
Thus, for example, the VZV virus is the responsible for varicella as a primary infection, whereas the reactivation of the latent virus in adults leads to herpes zoster. Herpes zoster affects the peripheral nerves and the skin, and can show serious complications, especially in individuals with alterations in their immune system.
EBV virus is the cause of infectious mononucleosis, particularly in adolescents. The EBV latent infection can be reactivated, especially in HIV-positive patients, resulting in the hairy leukoplakia. Also, the infection by said virus can lead to malignant lesions such as nasopharyngeal carcinoma, Burkitt's lymphoma, B cell lymphoma or oral carcinoma.
Cytomegalovirus infection can lead to the perinatal disease, acute HCMV infection, and to the worsening of opportunistic infections in immunocompromised subjects, for example, in transplanted or HIV infected patients.
The most frequent herpesviruses are herpes simplex HSV-1 and HSV-2, which are responsible for a large variety of infections involving vesicular eruptions on the skin and mucous membranes, and that can also occasionally affect the central nervous system and visceral organs.
HSV-1 infection is mainly associated with the orofacial region, causing infections from mild, such as herpes labialis, to severe, such as viral encephalitis. The most common injury associated with HSV-1 is herpes labialis, although it can also cause other pathologies such as, for example, primary herpetic gingivostomatitis, recurrent intraoral herpes and ocular herpes simplex.
HSV-2 causes injuries that are similar to oral herpes, but which occur mainly in the genital region (genital herpes), although it may also be involved in herpes labialis. The genital herpes has been associated with an increased risk of HIV transmission, and vice versa, due to the presence of genital ulcers.
Exceptionally, the reactivation or primary infection with herpes simplex virus can cause other serious and high mortality diseases, such as pneumonitis, hepatitis, tracheobronchitis or disseminated infection.
For its part, human papillomavirus (HPV) belongs to the family of Papillomaviridae, and are also DNA viruses which have a double-stranded DNA and are characterized for being non-enveloped.
To date, more than 100 different types of HPVs have been identified, which can be divided into cutaneous or mucosal, depending on the tissues susceptible to be infected, so that cutaneous HPVs infect and replicate in the squamous epithelium of the skin, causing warts, while mucosal HPVs infect and replicate in the mucosal membranes, resulting in genital, oral and conjunctival papillomas, as described for example in Woon-Won et al., Strategies against Human Papillomavirus infection and cervical cancer, J. Microbiol., 2004, 42 (4), pp 255-266.
HPV infection is often asymptomatic, so that it is estimated that in many individuals infected with this virus the infection is in a latent state.
HPV infection can cause a wide variety of clinical conditions, ranging from minor injuries to some types of cancers, especially cancer of the cervix (or cervical cancer), vaginal, anal, vulvar, penile or oropharyngeal cancers.
Benign infections associated with HPV are usually reduced to warts, of the plantar, common, flat or genital (condyloma) types.
HPV is considered the most common sexually transmitted viral disease worldwide, so about 30 sexually transmitted types have been identified, that primarily infect the neck of the womb (or cervix), vagina, vulva, penis and anus. They are often classified ranging from “low risk”, associated with genital warts, to “high risk”, associated with intraepithelial cervical lesions and cancers of the lower genital tract. Among the high-risk HPVs, four types stand out, that are those more often found in malignant cervical cancer cells, which are called type 16, 18, 31 and 45. It is believed that HPV is involved in practically all cases of cervical cancer.
Frequently, prior to the development of cervical cancer, premalignant or precancerous lesions appear, such as cervical dysplasia of the cervical cells, which can subside spontaneously, but involve some risk of becoming cancerous lesions.
Among the conditions of the mucous membranes, recurrent respiratory papillomatosis and focal epithelial hyperplasia (Heck's disease) may also be highlighted, as well as papillomas or carcinomas of the conjunctiva.
The greater or lesser severity of the pathologies derived from HPV infection is largely related to the immune level of infected patients, so an increased risk of developing HPV-derived neoplasms has been detected in HIV-infected patients or in transplanted patients.
Another opportunistic virus is the so called Molluscum contagiosum (MCV), a DNA virus belonging to the family of Poxviridae, whose infection causes the skin disease known as molluscum contagiosum, which causes papules or nodules.
The virus spreads by direct contact with lesions or through contaminated objects and also spreads by sexual contact. In patients with normal immune systems, the lesions usually disappear spontaneously after a certain period of time, but in immunocompromised individuals, the infection usually shows more severe and persistent clinical symptoms.
For its part, the JC virus or John Cunningham virus (JCV) is a DNA virus of the family of Polyomaviridae. Typically, the infection with this virus is asymptomatic and the virus remains latent in infected individuals.
However, when there are alterations in the immune system, typically in transplanted or HIV-positive patients, the JC virus can reactivate and lead to progressive multifocal leukoencephalopathy, a serious disorder that is characterized by the loss of myelin that covers and protects the nerves in the brain.
The BK virus is another opportunistic virus from the same family, which has a remarkable genetic similarity with the JC virus. Like that one, the infection in most of the infected population is mild or asymptomatic, but it can reactivate in immunocompromised patients, particularly in kidney transplant patients, in which it can lead to certain diseases such as hematuria, hemorrhagic cystitis, urethral stenosis and interstitial nephritis.
Finally, within the group of opportunistic viruses, it is worth mentioning hepatitis B virus (HBV), from the family of Hepadnaviridae, and hepatitis C virus (HCV), from the family of Flaviviridae.
Infection with hepatitis B virus can cause mild discomfort or be asymptomatic. It can also cause a chronic inflammation of the liver, and in that case it is known as a chronic hepatitis B, which can occasionally progress to cirrhosis and may increase the probability of contracting hepatocellular carcinoma. Hepatitis B spreads through contact with blood, semen or other fluids from an infected person.
Similarly, infection with hepatitis C virus can show mild symptoms or be asymptomatic, but chronic infection can lead to scarring of the liver, cirrhosis, and occasionally lead to liver cancer. The virus usually spreads through contact with infected blood.
Generally, there are no specific treatments entirely satisfactory for the disorders caused by these viruses, hence therapy is based on the use of certain antiviral products, and in some cases in vaccination, depending on the type of infection.
Thus, for example, the most widely used therapy for treating herpesvirus infections is aciclovir, especially for genital herpes, herpes labialis or herpes zoster, and it may be administered topically, orally or intravenously, depending on the type and severity of the pathology. Other antivirals that are also used as antiherpetics are, for example, valaciclovir, famciclovir, penciclovir, ganciclovir, foscarnet, and cidofovir, among others.
These drugs are not actually a cure that completely eliminates the herpesvirus infection from the organism, but rather they are used to mitigate the infection outbreaks, to help to reduce the pain and to make the symptoms disappear faster.
As for the human papillomavirus (HPV), currently there is no specific treatment for the infections caused by this virus. The main therapeutic strategies are based on the general stimulation of the cellular immune system, avoiding the replication, transcription and transformation of the virus, and the use of prophylactic vaccines and curative vaccines.
In the case of warts caused by this virus, as well as molluscum contagiosum, the treatment is based mainly on local removal methods, for example based on surgery, electrocautery, cryosurgery or laser therapy, which however can lead to the appearance of scarring and recurrence. Destructive chemical methods are also used, for example with trichloroacetic or bichloracetic acid, though such treatments cause irritation and are not uniformly effective. Antiviral products such as cidofovir or immunomodulators as imiquimod are also used topically, but they can also cause skin irritation.
For the treatment of cervical lesions associated with HPV, different antiviral and immunomodulatory agents have been used, particularly cidofovir, podophyllin, and also interferons. In recent years, efforts have focused primarily on the development of prophylactic vaccines for the prevention cervical cancer, as described in the article Gersch et al., New approaches to prophylactic human papillomavirus vaccines for cervical cancer prevention. Antivir. Ther., 2012, 17(3), pp 1-13. There is also a vaccine against hepatitis B virus (HBV).
None of the drugs available for the treatment of these viral infections has proved to be completely effective. Moreover, all of them have certain side effects. For example, antiviral drugs such as acyclovir, administered locally can cause irritation and burning, while administered orally, can occasionally lead to gastrointestinal disturbances, headache, and less frequently, renal insufficiency or neurotoxicity.
Moreover, continued use of antiviral drugs may cause resistance and lack of effectiveness in the long term. In this regard, different approaches have been disclosed in prior art for the treatment of infections caused by opportunistic viruses, including for example herpesvirus, with fewer side effects using therapies of natural origin based on the administration of certain amino acids and/or peptides.
Thus, for example, in the article A. R. Gaby, Natural Remedies for Herpes simplex, Altern. Med. Rev, 2006, 11 (2), 93-101, some alternative or complementary therapies to aciclovir for the treatment of herpes simplex infections are mentioned, among them the treatment with the amino acid lysine, which exerts an antagonistic mechanism on arginine, which is an amino acid required for the replication of herpes simplex virus.
Also, in the book chapter H. Jensen, Antimicrobial activity of lactoferrin and lactoferrin derived peptides, in: Dietary Protein Research Trends, J. R. Ling, editor, Nova Science Publishers, New York, 2007, chapter 1, pages 1-62, it is disclosed how the lactoferrin protein present in the milk serum, as well as some specific peptides derived therefrom, have antiviral activity against, among others, the HSV-1 and HSV-2 viruses.
In the German patent application DE-A-3922453 an extract prepared from a hydrolysate of the milk serum proteins is disclosed, which has antiherpetic properties. The proteins from which the hydrolysate is prepared can be alpha-lactalbumin, lactoferrin, beta-lactoglobulin, lysozyme, or serum albumin, all of them present in the milk serum. First, these proteins are hydrolyzed with at least one protease, for example, papain, pancreatin or chymotrypsin, and the residue obtained is extracted with a nonpolar solvent such as petroleum ether, benzene or toluene.
In the international patent application WO-A-92/17191 it is disclosed the use of the dipeptide L-Glu-L-Trp, called Thymogen®, for the treatment, in general, of opportunistic infections in immunocompromised patients, and in particular also for the treatment of herpes.
In the particular case of infections by the human papillomavirus, currently there are few therapeutic resources available for its treatment, although there are some publications in the state of the art in which some agents are proposed having therapeutic activity specifically for HPV infections.
Thus, in the article Mistry et al., The anti-papillomavirus activity of human and bovine lactoferricin, Antiviral Res, 2007, 75(3), pp 258-65, a study is disclosed showing the inhibitory activity against HPV-5 and HPV-16 virus infection of some peptides derived from bovine and human lactoferricin protein.
Furthermore, in the international patent application WO-A-00/01720 compositions for treating HPV infections are described, based on the administration of a relatively small peptide that is a peptidomimetic of the E2 protein, a HPV regulatory protein critical for DNA replication and its gene expression, so that these peptidomimetics act by preventing the formation of the complex between E1 and E2 factors, thereby inhibiting viral DNA replication and its proliferation.
Moreover, in the international patent application WO-A-2014/008248 pharmaceutical compositions based on chloroquine, hydroxychloroquine and/or amodiaquine are disclosed, for the treatment of infections associated with human papillomavirus, especially for the treatment of warts of the skin or anogenital warts, by topical or transdermal administration.
In view of the high incidence of infections by opportunistic viruses and the scarce effective therapeutic resources available to combat them, and also the occasionally serious consequences that may result from such infections, there remains a need for new drugs that are effective for the treatment of the pathologies associated with such viruses and that are also effective to prevent the pathological manifestations in infected individuals. Such drugs should be, at the same time effective, practical and safe, so that they involve a minimal risk of side effects.